Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc.
The NF-AT family of transcription factors activates early immune response genes such as cytokines. In the adult, NF-ATc is expressed exclusively in the lymphoid system and is induced upon lymphocyte activation. NF-ATc null mutant mice die in utero of cardiac failure, precluding analysis of the role of NF-ATc in lymphocyte activation. By using RAG-2-deficient blastocyst complementation, we now demonstrate that young, highly chimeric mice lacking NF-ATc have impaired repopulation of both thymus and peripheral lymphoid organs. Furthermore, NF-ATc deficiency impaired T lymphocyte activation and secretion of IL-4. B lymphocytes displayed reduced proliferation and a selective loss of IL-4-driven immunoglobulin isotypes both in vivo and in vitro. Our data demonstrate that NF-ATc is essential for the optimal generation and function of mature T and B lineage cells, with an especially profound effect on IL-4-driven responses.
Ranger
A M
AM
Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Hodge
M R
MR
Gravallese
E M
EM
Oukka
M
M
Davidson
L
L
Alt
F W
FW
de la Brousse
F C
FC
Hoey
T
T
Grusby
M
M
Glimcher
L H
LH
D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology*; D008099:Liver / Q000196:embryology / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C499308:Rag2 protein, mouse; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C064655:V(D)J recombination activating protein 2; D015847:Interleukin-4; D007073:Immunoglobulin E